1. Field of the Invention
The present invention relates to a preparation method of chromenone derivatives using radiation.
2. Description of the Related Art
Silybin is major active component of a thistle of the genus Silybum, a flowering plant of the daisy family (Asteraceae). Milk thistle has been used popularly over approximately 2000 years to treat liver diseases in Europe and other countries.
Studies report antioxidative and anticancer effect of silybin. Both in vitro and animal research suggest that silybin has hepatoprotective (antihepatotoxic) properties that protect liver cells against toxins. Silybin has also demonstrated anti-cancer effects against human prostate adenocarcinoma cells, estrogen-dependent and -independent human breast carcinoma cells, human ectocervical carcinoma cells, human colon cancer cells, and human lung carcinoma cells.
Dihydrosilybin is derivative of silybin, which has antioxidative activity, UV-protective effect, and furthermore, inhibitory activity against cytochrome P450 isoform CYP1A1 in human keratinocytes (HaCaT) and human hepatoma cells (HepG2).
Further, the recent study has suggested that dehydrosilybin (DHS) has higher inhibitory effect against granulocorpuscle lipid peroxidation, along with higher cell apoptosis effect, P-glycoprotein inhibitory effect and anticancer effect than silybin (Axel Huber, et. al., Biochimica et Biophysica Acta 1780 (2008) 837-847).
Further, apigenin is known to play a regulatory role in the mechanism of iNOS, COX-2, and NFκB activation (Lo, A. H. et al., Carcinogenesis 23(6): 983-991 (2002)), but leaves COX-1 uninhibited, thus used as arthritis treatment. Apigenin is also known to have a variety of biological activities including, antiinflammation, vasorelaxatory effect, antioxidation, antiviral activity, and anticancer activity. Regarding anticancer activity, in particular, apigenin can effectively act at a low concentration below approximately 50 μM for example, and act on the mechanism of apoptosis and necrosis in the cellular proliferation and angiogenesis, the representative characteristic of various cancers such as prostate cancer, breast cancer, lung cancer, colon cancer, blood cancer (leukemia), skin cancer, thyroid cancer, and liver cancer, to induce antiproliferative and cytotoxicity effect, thereby suppressing proliferation of cancer cells.
Apigenin is also reported to exert cytotoxicity effect and proliferation suppression activity such as accumulation of tumor suppressor protein p53 and inducement of cell apoptosis in nontumor cell such as murine embryo fibroblast as well as tumor cells. Apigenin is also known to exert some proliferation suppression effect in normal human prostatic endothelial cells (Plaumann B. et al., Oncogene 13(8), 1605-14 (1996) and Gupta, S. et al., Biochem. Biophys. Res. Commun. 287(4): 914-920).
However, recent study has also reported that while excellent effect is observed in in vitro test including cell line depending on concentration of apigenin per lung carcinoma cell line and colon carcinoma cell line, little effect is observed in vivo (Engelmann, C. et al., Phyto medicine 9(6): 489-495 (2002)).
To be specific, the effect of apigenin, based on the mechanism of suppressing cellular proliferation, includes both the cell proliferation suppression and cytotoxicity, and reacts very sensitively to effect at low concentration. Use of apigenin for articular cartilage restoration (Korean Patent No. 10-0437274).
Meanwhile, both dehydrosilybin and apigen are derived from natural product. These are usually isolated from the natural product for use in bioavailability measurement. For example, dehydrosilybin is prepared from commercially-available silybin via oxidation under potassium acetate (KOAc) dissolved in iodine and acetic acid (Barron, D., et. al., Bioorg Med Chem. Lett. 2000, 10(2), 157), and apigen can be prepared from naringenin (Jianli Chen, et. al., Carbohydrate Research 344 (2009) 2245-2249).
However, in these conventional synthetic compounds, it is impossible to obtain both dehydrosilybin and apigenin compounds at the same time, and the preparation of the compounds requires various reagents which are frequently hazardous to environment and pricy.
While researching for a compound preparation method which could overcome the shortcomings of the prior art mentioned above, the present inventors confirmed that it is possible to obtain both dehydrosilybin and apigenin compounds at the same time and without having to use reagents, by exposing commercially-available silybin in reactive solvent to radiation and thus completed the present invention.